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A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure–Associated Liver Disease in Preterm Yorkshire Piglets
Gastroenterology ( IF 29.4 ) Pub Date : 2023-05-30 , DOI: 10.1053/j.gastro.2023.05.035
Scott C Fligor 1 , Savas T Tsikis 1 , Thomas I Hirsch 1 , Amy Pan 2 , Kamila Moskowitzova 1 , Lorena Rincon-Cruz 1 , Ashlyn E Whitlock 1 , Paul D Mitchell 3 , Arthur P Nedder 4 , Kathleen M Gura 5 , David A Fraser 6 , Mark Puder 1
Affiliation  

Background & Aims

At least 20%–30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure–associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD.

Methods

Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179.

Results

Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist).

Conclusions

In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.



中文翻译:

中链脂肪酸类似物可预防早产约克夏仔猪肠衰竭相关的肝脏疾病

背景与目标

接受长期肠外营养的肠衰竭患者中至少有 20%–30% 会发展为肠衰竭相关性肝病 (IFALD),而对此的治疗选择很少。SEFA-6179 是一种一流的结构工程中链脂肪酸类似物,通过 GPR84、PPARα 和 PPARγ 激动发挥作用。我们假设 SEFA-6179 可以预防 IFALD 早产仔猪模型中的生化和组织学肝损伤。

方法

早产约克夏仔猪剖腹产,通过植入中心静脉导管提供肠外营养14天。动物用中链甘油三酯载体对照或 SEFA-6179 治疗。

结果

与出生后第 15 天的中链甘油三酯载体相比,SEFA-6179 可预防生化胆汁淤积(直接胆红素:1.9 vs <0.2 mg/dL,P = .01;总胆红素:2.7 vs 0.4 mg/dL  P =  .02 ;γ 谷氨酰转移酶:172 vs 30 U/L,P  = .01)。SEFA-6179 还可以预防脂肪变性(45.6 与 13.9 mg 甘油三酯/g 肝组织,P  = .009),减少胆管增殖(1.6% 与 0.5% 面积细胞角蛋白 7 阳性,P  = .009),并通过评估减少纤维化蒙面病理学家(Ishak 评分中位数:3 比 1,P  = 0.007)。肝组织的 RNA 测序表明 SEFA-6179 广泛影响炎症、代谢和纤维化途径,与其体外受体活性(GPR84/PPARα/PPARγ 激动剂)一致。

结论

在 IFALD 的早产仔猪模型中,SEFA-6179 治疗可预防生化胆汁淤积和脂肪变性,并减少胆管增殖和纤维化。SEFA-6179 是一种有前途的用于预防和治疗 IFALD 的一流疗法,将在即将进行的 II 期临床试验中进行研究。

更新日期:2023-05-30
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